When administered in standard intravenous or oral formulations, many pharmaceutical agents fail to reach the target organ in an effective concentration, or are not effective due to rapid elimination. This lack of effectiveness of the drug can result from a number of factors including: acid hydrolysis or incomplete absorption from the gastrointestinal tract, inability of the drug to cross physiological membranes such as the blood brain barrier, insufficient distribution to the site of action, enzymatic deactivation of the compound in the liver or blood prior to reaching the target organ, and/or rapid secretion of the drug into bile, urine or feces.
Delivery of drugs directly to the site of action using localized delivery systems provides advantages in that it provides high drug concentrations at the site of action while reducing systemic exposure. Indeed, in recent years it has been demonstrated that local administration offers increased efficacy and decreased toxicity of anti-neoplastic agents in the treatment of various cancers. Implantation of a biodegradable drug delivery device containing active drug substances could provide high local concentrations of the pharmaceutically active agent for a sustained period of time.
It is known that there is limited success in achieving cures for many prevalent diseases such as cancer, AIDS, infectious, immune or cardiovascular disorders using single therapeutic agents. Thus, combinations of therapeutic agents are generally used to combat life-threatening diseases such as AIDS and cancers. Indeed, numerous clinical trials have demonstrated enhanced efficacy and patient prognosis in cancer patients treated with combinations of anti-neoplastic agents. (Frei, et al., Clin. Cancer Res. (1998) 4:2027-2037; Todd, et al., J. Clin. Oncol. (1984) 2:986-993).
Often drug combinations demonstrate synergistic effects, with pronounced increases in total therapy efficacy. Synergistic combinations of agents have also been shown to reduce toxicity due to lower dose requirements, to reduce the development of multi-drug resistance (Shlaes, et al., Clin. Infect. Dis. (1993) 17:S527-S536) and to increase cancer cure rates (Barriere, et al., Pharmacotherapy (1992) 12:397-402; Schimpff, Support Care Cancer (1993) 1:5-18). By choosing agents which act by different mechanisms of action, multiple molecular or biochemical pathways can be averted, thus resulting in drug synergy (Shah and Schwartz, Clin. Cancer Res. (2001) 7:2168-2181).
Numerous studies have reported synergism in cancer therapy, with drug combinations exhibiting greater antineoplastic activity than the combined effects of either drug alone. Several of these include: Cisplatin and etoposide (Kanzawa, et al., Int. J. Cancer (1997) 71(3):311-319); L-canavanine and 5-fluorouracil (Swaffar, et al., Anti-Cancer Drugs (1995) 6:586-593), Vinblastine and recombinant interferon-P (Kuebler, et al., J. Interferon Res. (1990) 10:281-291); Cisplatin and carboplatin (Kobayashi, et al., Nippon Chiryo Gakkai Shi (1990) 25:2684-2692); Ethyl deshydroxy-sparsomycin and cisplatin or cytosine arabinoside (AraC) or methotrexate or 5-FU or vincristine (Hofs, et al., Anticancer Drugs (1994) 5:35-42); and Cisplatin and paclitaxel (Engblom, et al., Br. J. Cancer (1999) 79:286-292). To date, very few delivery systems have been developed for combinations of agents.
In order to achieve effective sustained concentrations of drugs at the target organs, the drug is usually combined with a carrier that is biocompatible and biodegradable. Suitable carriers for drug incorporation range in size from small molecules to macromolecules, including high molecular weight polymers. Polymer-based devices thus can be used to release a drug at a specific location at a controlled rate over a period of time. The most desirable polymeric matrix for drug delivery is one that is inexpensive, biocompatible, biodegradable, flexible and provides a uniform controlled release of the active substance in an aqueous environment. Chitosan based polymer blends are useful for controlled drug delivery because they degrade uniformly into non-toxic molecules that are non-mutagenic, non-cytotoxic, and non-inflammatory.
Chitosan is a natural, biodegradable cationic polysaccharide, which has previously been described as a promoter of wound healing (Balassa, 1972; Balassa, 1975). Chitosan is a commercially available inexpensive polymer which is mainly composed of D-glucosamine units that are generated through catalyzed N-deacetylation of chitin, a natural material extracted from fungi, the exoskeletons of shellfish and from algae. Chitosan has good viscoelastic properties with excellent tissue compatibility and biodegradability which renders it ideal for bioactive and resorbable implants. Moreover, chitin and partially-acetylated chitosan derivatives have been extensively investigated as implantable materials due to their favorable biocompatability and degradation to the simple amino acids; glucosamine and N-acetyl-glucosamine (Muzzarelli, 1999). Modified chitins and chitosans have been administered to humans in the form of dressings for wounded soft tissues and for the controlled delivery of drugs (Muzzarelli et al, 1986; 1999; Muzzarelli, 1993; 1996; Tokura and Azuma, 1992; Wada, 1995; Maekawa and Wada, 1990; Mita et al., 1989).
Chitosan based hydrogels may be designed for use as biomedical implants. The use of chitosan requires physical or chemical cross-linking in order to ensure stability in the biological milieu. Chitosan is a positively charged crystalline polymer that becomes increasingly soluble in medias of low pH (1% acetic acid solution, pH=5). The initial step in the film formation process is the dissolution of chitosan in acetic acid. In this step, chitosan becomes protonated as its amino groups on each polymer repeat unit becomes charged and associates with acetate counter-ions. During the drying process, water is driven out from the film, leaving the acetate molecule as a non-ionized salt. When the film is immersed in release buffer, ion exchange occurs, causing the film to swell rapidly. During the swelling of the film, acetic acid is released lowering the pH of the buffer and the film is quickly dissolved (Hoffman et. al, J. Control. Rel. (2001) 72:35-46).
Due to chitosans hydrophilic properties, most drug delivery applications uses “cross-linkers” in order to avoid this rapid dissolution (burst release) and provide stability (controlled drug release) in a biological milieu. Various cross-linking reagents have been used for chitosan gels. In the past, preparation of chitosan-based films used synthetic chemical cross-linking agents such as epoxy compounds and glutaraldehyde (Kawwamura et. al. Ind Eng Chem Res (1993), 32: 386-391; Rumunan-Lopez and R. Bodmeier, J. Control Rel. (1997); 44 215-225). Chemical cross-linking with aldehydes is not optimal for the encapsulation of proteins, peptides and other molecules with amino groups which can also undergo covalent cross-linkage. In addition, these synthetic cross-linking agents are highly cytotoxic, thus impairing the biocompatibility of these films (Nishi et al, Journal of Biomed Mater Res (1995); 29, 829-834).
Recently, various researchers have exploited non-covalent or physical cross-linking of chitosan polymer chains to achieve electrostatic and/or hydrogen bonding, thus increasing the stability and biocompatibility of the hydrogel. For example, negatively charged molecules such as oligonucleotides (DNA or RNA) engage in electrostatic interactions with chitosan to produce adducts that are stable for up to 15 days (Springate et al, (2003) Patent No. #20030134810). In addition, Hoffman et al. developed a physically cross-linked chitosan-glycerol film for the mucosal delivery of glycoproteins (Hoffman et. al, J. Control. Rel. (2001) 72:35-46).
The polymer-lipid or PoLi implant system is a physically cross-linked composition or system developed from natural ingredients (chitosan and lipid) and its stability can range from days to months depending on the formulation. The physical cross-linking within the PoLi implant is achieved through interactions between chitosan and phospholipid. Phospholipids such as phosphatidylcholine, phosphatidylethanolamine and phosphatidylglycerol are fat soluble entities that consist of lipophilic and hydrophilic components. These endogenous lipids are important components of cellular membranes in organisms and are involved in the solubilization of both hydrophilic and hydrophobic compounds.
In addition, due to the amphiphilic nature of the PoLi system it can be used for solubilization and delivery of both hydrophobic and hydrophilic agents. In this way, the PoLi formulation may be used for delivery of hydrophilic or hydrophobic drugs or combinations thereof.
Thus a biodegradable, biocompatible controlled drug delivery system or implant using a chitosan based material, the method of manufacturing this implant, the use of this implant in the delivery of pharmaceutically active agents is desirable.